Prodrugs of 4-((1r, 3s)-6-chloro-3-phenyl-2,3-dihydro-1h-inden-1-y)-1-,2,2-trimethylpiperazine and 4-((1r,3s)-6-chloro-3-(phenyl-d5)-2,3-dihydro-1h-inden-1yl)-2,2-dimethyl-1 (methyl-d3)piperazine

ABSTRACT

The present invention relates to prodrugs of 4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethylpiperazine in the form of 1a and 1b; and 4-((1R,3S)-6-chloro-3-(phenyl-d5)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d3)piperazine in the form of 2a and 2b, wherein X—is a counter ion, or pharmaceutically acceptable salts thereof. The present invention also provides pharmaceutical compositions comprising prodrugs, or pharmaceutically acceptable salts thereof, of the invention.

FIELD OF THE INVENTION

The present invention relates to prodrugs of4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethylpiperazinein the form of 1a and 1b; and4-((1R,3S)-6-chloro-3-(phenyl-d₅)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d₃)piperazinein the form of 2a and 2b, wherein X⁻ is a counter ion,

or pharmaceutically acceptable salts thereof.

The present invention also provides pharmaceutical compositionscomprising prodrugs, or pharmaceutically acceptable salts thereof, ofthe invention.

BACKGROUND OF THE INVENTION

A group of trans isomers of 3-aryl-1-(1-piperazinyl)indanes substitutedin the 2- and/or 3-position of the piperazine ring has been described inWO 93/22293 and in Klaus P. Bøgesø, Drug Hunting, the Me-dicinalChemistry of 1-Piperazino-3-phenylindans and Related Compounds, 1998,ISBN 87-88085-10-4 (cf. e.g. compound 69 in table 3, p. 47 and in table9A, p. 101). The compounds are described as having high affinity fordopamine D₁ and D₂ receptors and the 5-HT₂ receptor and are suggested tobe useful for treatment of several diseases in the central nervoussystem, including schizophrenia.

Trans racemic4-((6-chloro-3-phenyl-indan-1-yl)-1,2,2-trimethyl-piperazine may e.g. besynthesized analogously to the methods outlined in Bøgesø et al., J.Med. Chem., 1995, 38, p. 4380-4392 and in WO 93/22293. Manufacture ofthis compound by resolution of trans racemic4-((6-chloro-3-phenyl-indan-1-yl)-1,2,2-trimethyl-piperazine has beendescribed by Bøgesø et al. in J. Med. Chem., 1995, 38, p. 4380-4392, seetable 5, compound (−)-38. The process described comprises the use of(+)-ditoluoyl tartaric acid for resolution in ethylacetate, and thecompound is isolated as the fumarate salt.4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethylpiperazinehas subsequently been afforded the International Non-proprietary Name(INN) zicronapine by WHO. Salts of4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethylpiperazinehave been disclosed in WO 2005/016900, whereas later patent applicationsdisclose alternative methods for the manufacture of4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethylpiperazine(WO 2011/003423) and resolution of the same compound (WO 2012/093165).4-((1R,3S)-6-chloro-3-(phenyl-d₅)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d₃)piperazineis deuterium (²H) enriched4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethylpiperazinein the positions indicated in 2a and 2b.4-((1R,3S)-6-chloro-3-(phenyl-d₅)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d₃)piperazinehas been disclosed in WO 2012/176066, which also discloses syntheticroutes for obtaining4-((1R,3S)-6-chloro-3-(phenyl-d₅)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d₃)piperazine.

WO 2014/096151 discloses a further synthetic route for obtaining4-((1R,3S)-6-chloro-3-(phenyl-d₅)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d₃)piperazinevia conversion of 3,5-dichloro-1-(phenyl-d₅)-indan.

The present invention provides prodrugs of4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethylpiperazineand4-((1R,3S)-6-chloro-3-(phenyl-d₅)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d₃)piperazine.The prodrugs of the present invention may e.g. improve uptake of4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethylpiperazineand4-((1R,3S)-6-chloro-3-(phenyl-d₅)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d₃)piperazine,delay the release of4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethylpiperazineand4-((1R,3S)-6-chloro-3-(phenyl-d₅)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d₃)piperazine,or lower the level of possible adverse events.

SUMMARY OF THE INVENTION

The invention provides compounds that are prodrugs as shown below (1aand 1b; 2a and 2b):

and pharmaceutically acceptable salts thereof.

1a and 2a are R-configured at the chiral nitrogen atom, while 1b and 2bare S-configured at the chiral nitrogen atom.

In one embodiment, the present invention provides a prodrug as definedabove or a pharmaceutically acceptable salt thereof for use in therapy.

In one embodiment, the invention provides a pharmaceutical compositioncomprising a prodrug of the invention as defined above or apharmaceutically acceptable salt thereof and one or morepharmaceutically acceptable excipients.

In one embodiment, the present invention provides a prodrug as definedabove or a pharmaceutically acceptable salt thereof for use in a methodfor the treatment of a CNS disease.

In one embodiment, the invention provides the use of a prodrug asdefined above or a pharmaceutically acceptable salt thereof for use inthe manufacture of a medicament for the treatment of a CNS disease.

In one embodiment, the present invention provides a method for thetreatment of a CNS disease, the method comprising the administration ofa therapeutically effective amount of a prodrug as defined above or apharmaceutically acceptable salt thereof to a patient in need thereof.

DETAILED DESCRIPTION OF THE INVENTION

The invention provides compounds that are prodrugs as shown below (1aand 1b; 2a and 2b):

1a and 2a are R-configured at the chiral nitrogen atom, while 1b and 2bare S-configured at the chiral nitrogen atom.

R is linear or branched C₁-C₁₁ alkyl, such as methyl; or C₃-C₁₀cycloalkyl, such as cyclohexylmethyl or cyclohexylethyl.

—CH₂OC(O)R attached to4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethylpiperazineor4-((1R,3S)-6-chloro-3-(phenyl-d₅)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d₃)piperazineis referred to as the prodrug group.

X⁻ is selected from the group consisting of halide anion, such aschloride, bromide or iodide, C₁-C₁₀ sulfonate, optionally fluorinated,such as mesylate, tosylate, trifluoromethanesulfonate ornonafluorobutanesulfonate, and linear or branched C₁-C₁₁ carboxylate,optionally fluorinated, such as trifluoroacetate.

Compounds 1a and 1b have the natural hydrogen isotope distribution,while 2a and 2b are enriched in deuterium (²H) at the indicatedpositions.

Prodrug

A prodrug in general is a compound which may not have anypharmacological activity itself, but which upon administration to apatient is metabolised to provide a pharmacologically active compound.More specifically, a prodrug of the present invention is a compoundwhich upon administration to a patient is metabolised to provide4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethylpiperazine(prodrugs 1a and 1b) or4-((1R,3S)-6-chloro-3-(phenyl-d₅)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d₃)piperazine(prodrugs 2a and 2b).

Salts

Some of the prodrugs of the present invention may be provided aspharmaceutically acceptable acid addition salts. The termpharmaceutically acceptable salts includes salts formed with inorganicand/or organic acids such as hydrochloride acid, hydrobromide acid,phosphoric acid, nitrous acid, sulphuric acid, benzoic acid, citricacid, gluconic acid, lactic acid, maleic acid, succinic acid, tartaricacid, acetic acid, propionic acid, oxalic acid, maleic acid, fumaricacid, glutamic acid, pyroglutamic acid, salicylic acid, salicylic acid,saccharin and sulfonic acids, such as methanesulfonic acid,ethanesulfonic acid, toluenesulfonic acid and benzenesulfonic acid. Someof the acids listed above are di- or tri-acids, i.e. acids containingtwo or three acidic hydrogens, such as phosphoric acid, sulphuric acid,fumaric acid and maleic acid. Di- and tri-acids may form 1:1, 1:2 or 1:3(tri-acids) salts, i.e. a salt formed between two or three molecules ofthe compound of the present invention and one molecule of the acid.

Additional examples of useful acids and bases to form pharmaceuticallyacceptable salts can be found e.g. in Stahl and Wermuth (Eds) “Handbookof Pharmaceutical salts. Properties, selection, and use”, Wiley-VCH,2008.

Therapeutically Effective Amount

In the present context, the term “therapeutically effective amount” of acompound means an amount sufficient to cure, alleviate or partiallyarrest the clinical manifestations of a given disease and itscomplications in a therapeutic intervention comprising theadministration of said compound. An amount adequate to accomplish thisis defined as “therapeutically effective amount”. Effective amounts foreach purpose will depend on the severity of the disease or injury aswell as the weight and general state of the subject. A prodrug of thepresent invention is typically administered to achieve therapeuticeffect comparable to the administration of 1-60 mg4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethylpiperazineor4-((1R,3S)-6-chloro-3-(phenyl-d₅)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d₃)piperazine,such as 1-30 mg4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethylpiperazineor4-((1R,3S)-6-chloro-3-(phenyl-d₅)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d₃)piperazine,such as 5 mg, 10 mg, 15 mg or 20 mg calculated as the free base. Thismeans e.g. that “20 mg4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethylpiperazineor4-((1R,3S)-6-chloro-3-(phenyl-d₅)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d₃)piperazine”means 20 mg4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethylpiperazineor4-((1R,3S)-6-chloro-3-(phenyl-d₅)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d₃)piperazinefree base where the actual amount administered has to be adjusted forthe weight of the prodrug group and further adjusted for the weight ofthe counter ion.

In the present context, “treatment” or “treating” is intended toindicate the management and care of a patient for the purpose ofalleviating, arresting, partly arresting or delaying progress of theclinical manifestation of the disease, or curing the disease. Thepatient to be treated is preferably a mammal, in particular a humanbeing.

Diseases

In the present context, “CNS disease” is intended to indicate a diseasein the central nervous system. As disclosed in e.g. WO 2005/016900 andWO 2012/176066 the pharmacological profile of4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethylpiperazineand4-((1R,3S)-6-chloro-3-(phenyl-d₅)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d₃)piperazine(i.e. the parent form of 1a, 1b, 2a and 2b) is expected to also make thecompound useful in the treatment of CNS diseases, including but notlimited to psychosis, in particular schizophrenia or other diseasesinvolving psychotic symptoms, such as, e.g., Schizophrenia, TreatmentResistant Schizophrenia (TRS) Schizophreniform Disorder, SchizoaffectiveDisorder, Delusional Disorder, Brief Psychotic Disorder, SharedPsychotic Disorder as well other psychotic disorders or diseases thatpresent with psychotic symptoms, e.g. bipolar disorder, such as mania inbipolar disorder. Compounds and/or compositions of the invention canfurther be used in treatment of disorders such as those described in,for example, U.S. Pat. Nos. 5,807,855; 7,648,991; 7,767,683; 7,772,240;8,076,342; U.S. Patent Publication Nos. 2008/0269248; 2010/0069676;2011/0178094; 2011/0207744; WO 2005/016900; EP 0 638 073; and J. Med.Chem. 1995, 38, 4380-4392; each herein incorporated by reference in itsentirety. The invention also relates to the medical use of compounds ofthe present invention as combination therapy in conjunction with othertherapeutic agents such as those described in, for example, U.S. Pat.Nos. 5,807,855; 7,648,991; 7,767,683; 7,772,240; 8,076,342; U.S. PatentPublication Nos. 2008/0269248; 2010/0069676; 2011/0178094; 2011/0207744;WO 2005/016900; EP 0 638 073; and J. Med. Chem. 1995, 38, 4380-4392;each herein incorporated by reference in its entirety.

In the present context Treatment Resistant Schizophrenia is intended toindicate a lack of satisfactory clinical improvement despite twotreatments with antipsychotics of adequate dose and duration.

Pharmaceutical Composition

The pharmaceutical compositions may be specifically formulated foradministration by any suitable route such as the oral, rectal, nasal,buccal, sublingual, transdermal and parenteral (e.g. subcutaneous,intramuscular, and intravenous) route; the oral route being preferred.

It will be appreciated that the route will depend on the generalcondition and age of the subject to be treated, the nature of thecondition to be treated and the active ingredient.

In the present context, the term “excipient” or “pharmaceuticallyacceptable excipient” refers to pharmaceutical excipients including, butnot limited to, fillers, antiadherents, binders, coatings, colours,disintegrants, flavours, glidants, lubricants, preservatives, sorbents,sweeteners, solvents, vehicles and adjuvants.

The present invention also provides a pharmaceutical compositioncomprising a4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethylpiperazineprodrug (1a and 1b) or4-((1R,3S)-6-chloro-3-(phenyl-d₅)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d₃)piperazineprodrug (2a and 2b) or a pharmaceutically acceptable salt thereof. Thepharmaceutical compositions according to the invention may be formulatedwith pharmaceutically acceptable excipients in accordance withconventional techniques such as those disclosed in Remington, TheScience and Practice of Pharmacy, 22^(th) edition (2012), Edited byAllen, Loyd V., Jr.

Pharmaceutical compositions for oral administration include solid oraldosage forms such as tablets, capsules, powders and granules; and liquidoral dosage forms such as solutions, emulsions, suspensions and syrupsas well as powders and granules to be dissolved or suspended in anappropriate liquid. Solid oral dosage forms may be presented as discreteunits (e.g. tablets or hard or soft capsules), each containing apredetermined amount of the active ingredient, and preferably one ormore suitable excipients. Where appropriate, the solid dosage forms maybe prepared with coatings such as enteric coatings or they may beformulated so as to provide modified release of the active ingredientsuch as delayed or extended release according to methods well known inthe art. Where appropriate, the solid dosage form may be a dosage formdisintegrating in the saliva, such as for example an orodispersibletablet.

Examples of excipients suitable for solid oral formulation include, butare not limited to, microcrystalline cellulose, corn starch, lactose,mannitol, povidone, croscarmellose sodium, sucrose, cyclodextrin,talcum, gelatin, pectin, magnesium stearate, stearic acid and loweralkyl ethers of cellulose. Similarly, the solid formulation may includeexcipients for delayed or extended release formulations known in theart, such as glyceryl monostearate or hypromellose.

If solid material is used for oral administration, the formulation mayfor example be prepared by mixing the active ingredient with solidexcipients and subsequently compressing the mixture in a conventionaltableting machine; or the formulation may for example be placed in ahard capsule e.g. in powder, pellet or mini tablet form. The amount ofsolid excipient will vary widely but will typically range from about 25mg to about 1 g per dosage unit.

Liquid oral dosage forms may be presented as for example elixirs,syrups, oral drops or a liquid filled capsule. Liquid oral dosage formsmay also be presented as powders for a solution or suspension in anaqueous or non-aqueous liquid. Examples of excipients suitable forliquid oral formulation include, but are not limited to, ethanol,propylene glycol, glycerol, polyethylenglycols, poloxamers, sorbitol,polysorbate, mono and di-glycerides, cyclodextrins, coconut oil, palmoil, and water. Liquid oral dosage forms may for example be prepared bydissolving or suspending the active ingredient in an aqueous ornon-aqueous liquid, or by incorporating the active ingredient into anoil-in-water or water-in-oil liquid emulsion.

Further excipients may be used in solid and liquid oral formulations,such as colourings, flavourings and preservatives etc.

Pharmaceutical compositions for parenteral administration includesterile aqueous and nonaqueous solutions, dispersions, suspensions oremulsions for injection or infusion, concentrates for injection orinfusion as well as sterile powders to be reconstituted in sterilesolutions or dispersions for injection or infusion prior to use.Examples of excipients suitable for parenteral formulation include, butare not limited to water, coconut oil, palm oil and solutions ofcyclodextrins. Aqueous formulations should be suitably buffered ifnecessary and rendered isotonic with sufficient saline or glucose.

Other types of pharmaceutical compositions include suppositories,inhalants, creams, gels, dermal patches, implants and formulations forbuccal or sublingual administration.

It is requisite that the excipients used for any pharmaceuticalformulation comply with the intended route of administration and arecompatible with the active ingredients.

EMBODIMENTS OF THE INVENTION

The invention is described further in the following embodiments:

-   -   1. A prodrug of        4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethylpiperazine        (in the form of 1a and 1b) or        4-((1R,3S)-6-chloro-3-(phenyl-d₅)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d₃)piperazine        (in the form of 1a and 1b)

-   -   -   wherein X⁻ is a counter ion selected from the group            consisting of a halide anion, such as chloride, bromide or            iodide, C₁-C₁₀ sulfonate, optionally fluorinated, such as            mesylate, tosylate, trifluoromethanesulfonate or            nonafluorobutanesulfonate, and linear or branched C₁-C₁₁            carboxylate, optionally fluorinated, such as            trifluoroacetate; or a pharmaceutically acceptable salt            thereof.

    -   2. The prodrug according to embodiment 1, wherein R is selected        from the group consisting of linear or branched C₁-C₁₁ alkyl and        C₃-C₁₀ cycloalkyl, or a pharmaceutically acceptable salt        thereof.

    -   3. The prodrug according to any of embodiments 1 and 2, wherein        R is selected from the group consisting of methyl, tertbutyl,        n-undecane and cyclohexylmethyl, or a pharmaceutically        acceptable salt thereof.

    -   4. The prodrug according to any of embodiments 1 to 3, wherein        the pharmaceutically acceptable salt is formed from        hydrochloride acid, hydrobromide acid, phosphoric acid, nitrous        acid, sulphuric acid, benzoic acid, citric acid, gluconic acid,        lactic acid, maleic acid, succinic acid, tartaric acid, acetic        acid, propionic acid, oxalic acid, maleic acid, fumaric acid,        glutamic acid, pyroglutamic acid, salicylic acid, salicylic        acid, saccharin and sulfonic acids, such as methanesulfonic        acid, ethanesulfonic acid, toluenesulfonic acid and        benzenesulfonic acid.

    -   5. The prodrug according to any of embodiments 1 to 4 selected        from the group consisting of        (R)-1-(acetoxymethyl)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethylpiperazin-1-ium,        (S)-1-(acetoxymethyl)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethylpiperazin-1-ium,        (R)-1-(acetoxymethyl)-4-((1R,3S)-6-chloro-3-(phenyl-d₅)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d₃)piperazin-1-ium,        (S)-1-(acetoxymethyl)-4-((1R,3S)-6-chloro-3-(phenyl-d₅)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d₃)piperazin-1-ium,        (R)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-methyl-1-((pivaloyloxy)methyl)piperazin-1-ium,        (S)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-methyl-1-((pivaloyloxy)methyl)piperazin-1-ium,        (R)-4-((1R,3S)-6-chloro-3-(phenyl-d₅)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d₃)-1-((pivaloyloxy)methyl)piperazin-1-ium,        (S)-4-((1R,3S)-6-chloro-3-(phenyl-d₅)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d₃)-1-((pivaloyloxy)methyl)piperazin-1-ium,        (R)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1-((dodecanoyloxy)methyl)-1,2,2-trimethylpiperazin-1-ium,        (S)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1-((dodecanoyloxy)methyl)-1,2,2-trimethylpiperazin-1-ium,        (R)-4-((1R,3S)-6-chloro-3-(phenyl-d₅)-2,3-dihydro-1H-inden-1-yl)-1-((dodecanoyloxy)methyl)-2,2-dimethyl-1-(methyl-d₃)piperazin-1-ium,        (S)-4-((1R,3S)-6-chloro-3-(phenyl-d₅)-2,3-dihydro-1H-inden-1-yl)-1-((dodecanoyloxy)methyl)-2,2-dimethyl-1-(methyl-d₃)piperazin-1-ium,        (R)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1-((2-cyclohexylacetoxy)methyl)-1,2,2-trimethylpiperazin-1-ium,        (S)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1-((2-cyclohexylacetoxy)methyl)-1,2,2-trimethylpiperazin-1-ium,        (R)-4-((1R,3S)-6-chloro-3-(phenyl-d₅)-2,3-dihydro-1H-inden-1-yl)-1-((2-cyclohexylacetoxy)methyl)-2,2-dimethyl-1-(methyl-d₃)piperazin-1-ium,        (S)-4-((1R,3S)-6-chloro-3-(phenyl-d₅)-2,3-dihydro-1H-inden-1-yl)-1-((2-cyclohexylacetoxy)methyl)-2,2-dimethyl-1-(methyl-d₃)piperazin-1-ium,        each of which is combined with a counter ion selected from the        group consisting of halide anion, such as chloride, bromide or        iodide, C₁-C₁₀ sulfonate, optionally fluorinated, such as        mesylate, tosylate, trifluoromethanesulfonate or        nonafluorobutanesulfonate, and linear or branched C₁-C₁₁        carboxylate, optionally fluorinated, such as trifluoroacetate;        or a pharmaceutically acceptable salt thereof.

    -   6. A pharmaceutical composition comprising any of the prodrugs        of embodiments 1 to 5, or a pharmaceutically acceptable salt        thereof, and one or more pharmaceutically acceptable excipients.

    -   7. The compound according to any of embodiments 1 to 5, or a        pharmaceutically acceptable salt thereof, or the pharmaceutical        composition according to embodiment 6 for use in therapy.

    -   8. Use of a compound according to any of embodiments 1 to 5 or a        salt thereof, or a pharmaceutical composition according to        embodiment 6 for the manufacture of a medicament for the        treatment of a Central Nervous System (CNS) disease.

    -   9. A compound according to any of embodiments 1 to 5 or a        pharmaceutical composition according to embodiment 6 for use in        a method for the treatment of a CNS disease.

    -   10. A method for the treatment of a CNS disease, the method        comprising the administration of a therapeutically effective        amount of a compound according to any of embodiments 1 to 5 or a        pharmaceutical composition according to embodiment 6 to a        patient in need thereof.

EXAMPLES Compounds of the Invention

The compounds of the invention can be prepared from either4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethylpiperazine(1) or4-((1R,3S)-6-chloro-3-(phenyl-d₅)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d₃)piperazine(2) both of which are described in the prior art as discussed above:

These compounds can be alkylated at the non-benzylic piperazine nitrogenatom by treatment with alkylating agents 3 either directly or viain-situ Finkelstein displacement of Y with a more reactive halogen suchas conversion from Y═Cl to Y═I by addition of sodium iodide or from Y═Clto Y═Br by addition of tetra-n-butyl ammonium bromide or sodium bromide.The reaction will afford a mixture of N-diastereoisomers 1a/1b or 2a/2b,depending on whether 1 or 2 is employed as substrate. TheseN-diastereoisomers can be separated either by recrystallization and/orby chiral chromatography using either high-performance liquidchromatography (HPLC), super-critical fluid chromatography (SFC), orsimulated moving bed chromatography (SMB). The anion Y⁻ can be exchangedwith X⁻ using for example ion exchange resin. Y⁻ can be selected fromthe same list as X⁻ as defined above. The order of the last twooperations can be reversed, and both steps can be performed severaltimes. The alkylating agents 3 are either commercially available such as3b from CombiBlocks (catalog number QC-7757) or can be prepared in asimilar manner as described in the specification for 3a or as describedin the literature (for sulfonates, see e.g. WO 2012/137225).

Methods Employed in the Preparation of the Prodrugs of the Invention.

The following methods were employed for high-performance liquidchromatography (HPLC), liquid chromatography/mass spectrometry (LC/MS),supercritical fluid chromatography (SFC), and ion exchange.

Method 1:

HPLC performed on a Agela-HP-q-p600 instrument fitted with a AgelaInnoval ods 250×80 mm column (10 microm particle size; columntemperature 20° C.). Eluent: 0.05% aq. HCl/acetronitrile 4:1 to 1:1 over20 min with a flow rate of 150 mL/min.

Method 2:

LC/MS performed on a Agilent 1200 & 1956A Instrument fitted with aPhenomenex Luna C18(2) 50×2 mm column (5 microm particle size; columntemperature 40° C.). Eluent: 0.037% trifluoroacetic acid in water/0.018%trifluoroacetic acid in acetonitrile 1:0 for 0.8 min; 1:0 to 2:3 over6.2 min; 2:3 for 3 min; 2:3 to 1:0 over 0.1 min with a flow rate of 0.6mL/min.

Method 3:

HPLC performed on a Agela-HP-q-p600 instrument fitted with a PhenomenexLuna C18 250×50 mm column (10 microm particle size; column temperature20° C.). Eluent: 0.05% aq. HCl/acetronitrile 4:1 to 1:1 over 20 min witha flow rate of 80 mL/min.

Method 4:

SFC performed with stacked injections on a Thar SFC80 preparativeinstrument fitted with a Chiralpak AD-H 250×30 mm column (particle size5 microm) operated at 40° C. Eluent: CO₂/0.1% trifluoroacetic acid inmethanol 7:3 for 5 min with a flow rate of 70 g/min. System backpressure 100 bar.

Method 5:

SFC performed on a Thar Analytical SFC instrument fitted with aChiralpak AD-3 100×4.6 mm column (particle size 3 microm; columntemperature 40° C.). Eluent: CO₂/0.05% isopropyl amine in methanol 95:5to 3:2 over 5 min with a flow rate of 4.0 mL/min. System back pressure100 bar.

Method 6:

SFC Performed as method 4 with a run time of 7 min.

Method 7:

LC/MS performed on a Agilent 1200 & MS 1956A Instrument fitted with aPhenomenex Luna C18(2) 50×2 mm column (5 microm particle size; columntemperature 40° C.). Eluent: 0.037% trifluoroacetic acid in water/0.018%trifluoroacetic acid in acetonitrile 9:1 for 0.4 min; 9:1 to 0:1 over3.0 min; 0:1 for 0.45 min; 0:1 to 9:1 over 0.01 min; 9:1 for 0.64 minwith a flow rate of 0.8 mL/min.

Method 8:

HPLC performed as method 3 but with 3:2 to 3:7 eluent gradient over 20min.

Method 9:

SFC performed with stacked injections on a Thar SFC80 preparativeinstrument fitted with a Chiralpak AD-H 250×30 mm column (particle size5 microm; column temperature 40° C.). Eluent: CO₂/0.1% trifluoroaceticacid in methanol 4:1 for 6 min with a flow rate of 70 g/min. System backpressure 100 bar.

Method 10:

SFC performed on a Waters Acquity UPC2 instrument fitted with aChiralpak AD-3 150×4.6 mm column (particle size 3 microm; columntemperature 35° C.). Eluent: CO₂/0.05% isopropyl amine in methanol 3:2over 6 or 10 min with a flow rate of 2.5 mL/min. System back pressure1500 psi.

Method 11:

Ion exchange performed using anion exchange resins in chloride form(717; Domestic 10024160) ion exchange resin. The sample was dissolved ina 1:1 mixture of acetonitrile and water and the solution was allowed topass slowly through a column with the resin (using ca six times as muchresin and sample). Acetonitrile/water (1:1) was added until all samplehad been eluted. The combined product fractions were concentrated invacuo and freeze-dried to afford the chloride salts of the compound(s).

Method 12:

LC/MS performed on a Agilent 1200 & MS 1956A Instrument fitted with aPhenomenex Luna C18(2) 50×2 mm column (5 microm particle size; columntemperature 40° C.). Eluent: 0.037% trifluoroacetic acid in water/0.018%trifluoroacetic acid in acetonitrile 99:1 to 1:9 over 3.4 min; 1:9-0:1over 0.45 min; 0:1 to 99:1 over 0.01 min; 991:1 for 0.64 min with a flowrate of 0.8 mL/min.

Method 13:

LC/MS performed on a Agilent 1200 & MS 1956A Instrument fitted with aPhenomenex Luna C18(2) 50×2 mm column (5 microm particle size; columntemperature 40° C.). Eluent: 0.037% trifluoroacetic acid in water/0.018%trifluoroacetic acid in acetonitrile 3:2 to 0:1 over 3.4 min; 0:1 for0.45 min; 0:1 to 3:2 over 0.01 min; 3:2 for 0.64 min with a flow rate of0.8 mL/min.

Method 14:

LC/MS performed on a Agilent 1200 & MS 6120 Instrument fitted with aPhenomenex Luna C18(2) 50×2 mm column (5 microm particle size; columntemperature 40° C.). Eluent: 0.037% trifluoroacetic acid in water/0.018%trifluoroacetic acid in acetonitrile 3:1 to 0:1 over 3.4 min; 0:1 for0.45 min; 0:1 to 3:1 over 0.01 min; 3:1 for 0.64 min with a flow rate of0.8 mL/min.

Method 15:

LC/MS performed on a Agilent 1200 & MS 6120B Instrument fitted with aPhenomenex Luna C18(2) 50×2 mm column (5 microm particle size; columntemperature 40° C.). Eluent: 0.037% trifluoroacetic acid in water/0.018%trifluoroacetic acid in acetonitrile 9:1 to 1:4 over 4.0 min; 1:4 for2.0 min; 1:4 to 9:1 over 0.01 min; 9:1 for 2.0 min with a flow rate of0.8 mL/min.

Method 16:

SFC performed as method 9 with a run time of 8 min.

Method 17:

LC/MS performed on a Agilent 1200 & MS 1956A Instrument fitted with aPhenomenex Luna C18(2) 50×2 mm column (5 microm particle size; columntemperature 40° C.). Eluent: 0.037% trifluoroacetic acid in water/0.018%trifluoroacetic acid in acetonitrile 1:0 for 0.8 min; 1:0 to 2:3 over6.2 min; 2:3 for 3 min; 2:3 to 1:0 over 0.1 min with a flow rate of 0.8mL/min.

Method 18:

Reverse-phase column chromatography performed on a Biotage Oneinstrument fitted with a Agela 40×10 cm (20-40 nM) C18 column at 25° C.Eluent: water and 0.4% concentrated hydrochloric acid 7:3 to 3:7 over 30min; 3:7 for 25 min; 0:1 for 10 min with a flow rate of 120 mL/min.

Example 1: Preparation of Iodomethyl Acetate (Alkylating Agent 3a)

To a mixture of NaI (29.0 g) and acetonitrile (140 mL) was addedchloromethyl acetate (3a1; 20.0 g) dropwise at 20° C. in the dark. Thereaction was stirred at ambient temperature for 24 hours. The resultingmixture was partitioned between methyl tert-butyl ether (MTBE; 160 mL)and water (200 mL), and the aqueous layer was extracted with MTBE (150mL). The combined organic layers were washed successively with saturatedaqueous sodium bicarbonate (200 mL), 10 percent aqueous sodium sulfitesolution (200 mL), and saturated aqueous sodium chloride (100 mL) beforeit was dried over sodium sulphate, filtered, and concentrated to affordiodomethyl acetate (3a; 15.5 g) sufficiently pure for the next step.

Example 2: Preparation of Iodomethyl n-Dodecanoate (Alkylating Agent 3c)

n-Dodecanoyl chloride (3c2; 80.0 g) was added slowly to a mixture ofparaformaldehyde (22.0 g) and zinc chloride (24.9 g) in acetonitrile(550 mL) at −10° C. under an argon atmosphere. The reaction mixture wasstirred at this temperature for 1 hour and at ambient temperature for 18hours. The crude reaction mixture was directly purified by column flashchromatography on silica gel (gradient eluent: petroleum ether/ethylacetate 50/1 to 2/1) to afford chloromethyl n-dodecanoate (3c1; 45.4 g)sufficiently pure for the next step. To a mixture of sodium iodide (32.5g) in acetonitrile (300 mL) was added compound 3c1 (45.0 g) dropwise atambient temperature in the dark. The reaction was stirred at ambienttemperature for 24 hours. The crude mixture was partitioned between MTBE(300 mL) and water (300 mL), and the aqueous layer was extracted withMTBE (100 mL). The combined organic layers were washed successively withsaturated aqueous sodium bicarbonate (200 mL), 10 percent aqueous sodiumsulfite solution (150 mL), and saturated aqueous sodium chloride (150mL) before it was dried over sodium sulphate, filtered, and concentratedto afford iodomethyl n-dodecanoate (3c; 51.0 g) sufficiently pure forthe next step.

Example 3: Preparation of Iodomethyl 2-cyclo-hexylacetate (AlkylatingAgent 3d)

Thionyl chloride (69 mL) was added to a solution of 2-cyclo-hexylaceticacid (3d3; 44.8 g) in toluene (180 mL) under an argon atmosphere, andthe mixture was stirred at 110° C. for 12 hours. The volatiles wereremoved in vacuo to afford 2-cyclo-hexylacetyl chloride (3d2; 42.3 g)sufficiently pure for the next step. 2-Cyclo-hexylacetyl chloride (3d2;48.6 g—combined material from the previous step and another batch) wasadded to a solution of zinc chloride (20.6 g) and paraformaldehyde (18.2g) in acetonitrile (336 mL) at −10° C. under an argon atmosphere. Thereaction mixture was stirred at −10° C. for one hour and then at ambienttemperature for 18 hours. The volatiles were removed in vacuo. Theresidue was purified by column flash chromatography on silica gel(gradient eluent: petroleum ether/ethyl acetate I/O to 0/1) to affordchloromethyl 2-cyclo-hexylacetate (3d1; 24.0 g) sufficiently pure forthe next step. To a solution of sodium iodide (18.1 g) in acetonitrile(126 mL) was added 2-cyclo-hexylacetate (3d1; 21.9 g) dropwise atambient temperature in the dark. The reaction was stirred at ambienttemperature for 24 hours. The crude mixture was partitioned between MTBE(200 mL) and water (200 mL), and the aqueous layer was extracted withMTBE (150 mL). The combined organic layers were washed successively withsaturated aqueous sodium bicarbonate (200 mL), 10 percent aqueous sodiumsulfite solution (200 mL), and saturated aqueous sodium chloride (100mL) before it was dried over sodium sulphate, filtered, and concentratedto afford iodomethyl 2-cyclo-hexylacetate (3d; 27.0 g) sufficiently purefor the next step.

Example 4: Preparation of Acetoxymethyl 1a and 1b

A solution of4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethylpiperazine(1; 6.0 g) in acetonitrile (42 mL) was heated to 80° C. beforeiodomethyl acetate (3a; 6.76 g) was added. The mixture was stirred at80° C. for 1 hour before the volatiles were removed in vacuo. Theresidual solid was suspended in MTBE (25 mL) and then filtered off. Thefilter cake was washed with MTBE (15 mL) and dried to afford ca. 8 g ofa mixture of(R)-1-(acetoxymethyl)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethylpiperazin-1-iumiodide (1a1; X═I⁻) and(S)-1-(acetoxymethyl)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethylpiperazin-1-iumiodide (1b1; X═I⁻). This material was converted from the iodide salt tothe corresponding chloride salts by ion exchange (method 11) to affordthe crude chloride salts of 1a1; X═Cl⁻ and 1b1; X═Cl⁻. This material waspurified by preparative HPLC (method 1) to give a mixture of(R)-1-(acetoxymethyl)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethylpiperazin-1-iumchloride and(S)-1-(acetoxymethyl)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethylpiperazin-1-iumchloride (1a1; X═Cl⁻ and 1b1; X═Cl⁻; 3 g).

¹H NMR: 400 MHz Methanol-d₄ 7.56 (broad s, 1H), 7.29 (t, J=7.2 Hz, 3H),7.25-7.18 (m, 1H), 7.14-7.09 (m, 2H), 6.96 (d, J=7.9 Hz, 1H), 5.50(broad s, 1H), 5.44-5.33 (m, 1H), 4.72 (broad s, 1H), 4.60-4.48 (m, 1H),3.78 (broad d, J=5.7 Hz, 1H), 3.66 (broad s, 1H), 3.19-2.81 (m, 8H),2.26 (s, 4H), 1.71-1.57 (m, 6H).

LC/MS (method 17): retention time 6.60 min, 86.5% UV purity (220 nm),m/z mass observed 427.1.

Example 5: Preparation of Acetoxymethyl 2a and 2b

Mixtures of(R)-1-(acetoxymethyl)-4-((1R,3S)-6-chloro-3-(phenyl-d₅)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d₃)piperazin-1-iumiodide and(S)-1-(acetoxymethyl)-4-((1R,3S)-6-chloro-3-(phenyl-d₅)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d₃)piperazin-1-iumiodide (2a1; X═I⁻ and 2b1; X═I⁻) and(R)-1-(acetoxymethyl)-4-((1R,3S)-6-chloro-3-(phenyl-d₅)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d₃)piperazin-1-iumchloride and(S)-1-(acetoxymethyl)-4-((1R,3S)-6-chloro-3-(phenyl-d₅)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d₃)piperazin-1-iumchloride (2a1; X═Cl⁻ and 2b1; X═Cl⁻) were prepared in a similar manneras 1a1 and 1b1. The synthesis started from4-((1R,3S)-6-chloro-3-(phenyl-d₅)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d₃)piperazine(2; 6.50 g) and iodomethyl acetate (3a; 7.16 g) in acetonitrile (45.0mL) to afford ca. 8 g of crude iodide and 2.00 g of HPLC-purified(method 1) mixture of(R)-1-(acetoxymethyl)-4-((1R,3S)-6-chloro-3-(phenyl-d₅)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d₃)piperazin-1-iumchloride and(S)-1-(acetoxymethyl)-4-((1R,3S)-6-chloro-3-(phenyl-d₅)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d₃)piperazin-1-iumchloride (2a1; X═Cl⁻ and 2b1; X═Cl⁻).

¹H NMR: 400 MHz Methanol-d₄ 7.61-7.54 (m, 1H), 7.34-7.28 (m, 1H), 6.96(d, J=8.3 Hz, 1H), 5.51 (broad d, J=12.7 Hz, 1H), 5.47-5.35 (m, 1H),4.74 (broad s, 1H), 4.56 (broad s, 1H), 3.77 (broad s, 1H), 3.68 (broads, 1H), 3.27-2.78 (m, 5H), 2.26 (d, J=0.9 Hz, 4H), 1.73-1.58 (m, 6H).

LC/MS (method 17): retention time 6.56 min, 93.5% UV purity (220 nm),m/z mass observed 435.2.

Example 6: Preparation of Pivaloyloxymethyl 1a and 1b

Mixtures of(R)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethyl-1-((pivaloyloxy)methyl)piperazin-1-iumiodide and(S)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethyl-1-((pivaloyloxy)methyl)piperazin-1-iumiodide (1a2; X═I⁻ and 1b2; X═I⁻) and(R)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethyl-1-((pivaloyloxy)methyl)piperazin-1-iumchloride and(S)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethyl-1-((pivaloyloxy)methyl)piperazin-1-iumchloride (1a2; X═Cl⁻ and 1b2; X═Cl⁻) were prepared in a similar manneras 1a1 and 1b1. The synthesis started from4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethylpiperazine(1; 4.6 g) and iodomethyl pivalate (3b; 6.27 g) in acetonitrile (32 mL)to afford ca. 5 g crude iodide and ca. 4 g HPLC-purified (method 3)mixture of(R)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-methyl-1-((pivaloyloxy)methyl)piperazin-1-iumchloride and(S)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-methyl-1-((pivaloyloxy)methyl)piperazin-1-iumchloride (1a2; X═Cl⁻ and 1b2; X═Cl⁻). This mixture was separated bychiral SFC (method 4). The two products were purified as before usingmethods 11 and 3 to afford two products:

First eluting isomer: 1.00 g of either(R)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethyl-1-((pivaloyloxy)methyl)piperazin-1-iumchloride (1a2; X═Cl⁻) or(S)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethyl-1-((pivaloyloxy)methyl)piperazin-1-iumchloride (1b2; X═Cl⁻).

¹H NMR: 400 MHz Methanol-d₄ 7.71 (broad s., 1H), 7.39-7.27 (m, 3H),7.26-7.19 (m, 1H), 7.18-7.10 (m, 2H), 6.97 (d, J=8.4 Hz, 1H), 5.70-5.57(m, 1H), 5.52 (d, J=8.8 Hz, 1H), 4.93 (broad s., 1H), 4.69 (t, J=7.6 Hz,1H), 3.85 (broad s., 2H), 3.50-3.31 (m, 4H), 3.16 (s, 3H), 3.05-2.92 (m,1H), 2.42-2.28 (m, 1H), 1.71 (broad s, 6H), 1.31 (s, 9H).

LC/MS (method 12): retention time 3.12 min, 98.5% UV purity (220 nm),m/z mass observed 469.2.

SFC (method 5): retention time 1.91 min, >99% UV purity (220 nm).

Second eluting isomer: 0.80 g of either(S)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethyl-1-((pivaloyloxy)methyl)piperazin-1-iumchloride (1b2; X═Cl⁻) or(R)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethyl-1-((pivaloyloxy)methyl)piperazin-1-iumchloride (1a2; X═Cl⁻).

¹H NMR: 400 MHz Methanol-d₄ 7.69 (broad s., 1H), 7.37-7.26 (m, 3H),7.26-7.18 (m, 1H), 7.14 (d, J=7.2 Hz, 2H), 6.96 (d, J=8.4 Hz, 1H),5.58-5.40 (m, 2H), 4.90 (broad s., 1H), 4.65 (broad s., 1H), 3.94 (broads., 1H), 3.70 (d, J=14.0 Hz, 1H), 3.36 (broad s., 3H), 3.22 (broad s.,3H), 3.16-2.90 (m, 2H), 2.39-2.25 (m, 1H), 1.79-1.56 (m, 6H), 1.31 (s,9H).

LC/MS (method 7): retention time 2.72 min, 97% UV purity (220 nm), m/zmass observed 469.2.

SFC (method 5): retention time 2.36 min, >96% UV purity (220 nm).

Example 7: Preparation of Pivaloyloxymethyl 2a and 2b

Mixtures of(R)-4-((1R,3S)-6-chloro-3-(phenyl-d₅)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d₃)-1-((pivaloyloxy)methyl)piperazin-1-iumiodide and(S)-4-((1R,3S)-6-chloro-3-(phenyl-d₅)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d₃)-1-((pivaloyloxy)methyl)piperazin-1-iumiodide (2a2; X═I⁻ and 2b2; X═I⁻) and(R)-4-((1R,3S)-6-chloro-3-(phenyl-d₅)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d₃)-1-((pivaloyloxy)methyl)piperazin-1-iumchloride and(S)-4-((1R,3S)-6-chloro-3-(phenyl-d₅)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d₃)-1-((pivaloyloxy)methyl)piperazin-1-iumchloride (2a2; X═Cl⁻ and 2b2; X═Cl⁻) were prepared in a similar manneras 1a1 and 1b1. The synthesis started from4-((1R,3S)-6-chloro-3-(phenyl-d₅)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d₃)piperazine(2; 6.00 g) and iodomethyl pivalate (3b; 8.00 g) in acetonitrile (42 mL)to afford ca. 5 g crude iodide and ca. 4 g HPLC-purified (method 3)mixture of(R)-4-((1R,3S)-6-chloro-3-(phenyl-d₅)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d₃)-1-((pivaloyloxy)methyl)piperazin-1-iumchloride and(S)-4-((1R,3S)-6-chloro-3-(phenyl-d₅)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d₃)-1-((pivaloyloxy)methyl)piperazin-1-iumchloride (2a2; X═Cl⁻ and 2b2; X═Cl⁻). This mixture was separated bychiral SFC (method 6). The two products were purified as before usingmethods 11 and 3 to afford two products:

First eluting isomer: 1.00 g of either(R)-4-((1R,3S)-6-chloro-3-(phenyl-d₅)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d₃)-1-((pivaloyloxy)methyl)piperazin-1-iumchloride (2a2; X═Cl⁻) or(S)-4-((1R,3S)-6-chloro-3-(phenyl-d₅)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d₃)-1-((pivaloyloxy)methyl)piperazin-1-iumchloride (2b2; X═Cl⁻).

¹H NMR: 400 MHz Methanol-d₄ 7.71 (broad s, 1H), 7.36 (dd, J=2.0, 8.1 Hz,1H), 6.97 (d, J=7.9 Hz, 1H), 5.61 (broad s, 1H), 5.52 (d, J=8.8 Hz, 1H),5.00-4.89 (m, 1H), 4.68 (s, 1H), 3.85 (broad s, 2H), 3.54-3.31 (m, 3H),3.28-3.16 (m, 1H), 2.99 (broad dd, J=10.3, 13.8 Hz, 1H), 2.43-2.28 (m,1H), 1.71 (broad s, 6H), 1.32 (s, 9H).

LC/MS (method 7): retention time 2.72 min, 98.9% UV purity (220 nm), m/zmass observed 477.3.

SFC (method 5): retention time 1.79 min, >99% UV purity (220 nm).

Second eluting isomer: 0.72 g of either(S)-4-((1R,3S)-6-chloro-3-(phenyl-d₅)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d₃)-1-((pivaloyloxy)methyl)piperazin-1-iumchloride (2b2; X═Cl⁻) or(R)-4-((1R,3S)-6-chloro-3-(phenyl-d₅)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d₃)-1-((pivaloyloxy)methyl)piperazin-1-iumchloride (2a2; X═Cl⁻).

¹H NMR: 400 MHz Methanol-d₄ 7.44 (d, J=2.2 Hz, 1H), 7.25 (dd, J=2.0, 8.1Hz, 1H), 6.94 (d, J=8.3 Hz, 1H), 5.52-5.45 (m, 1H), 5.45-5.39 (m, 1H),4.58 (dd, J=3.9, 7.9 Hz, 1H), 4.46 (t, J=7.7 Hz, 1H), 3.74 (broad s,1H), 3.53 (broad d, J=12.7 Hz, 1H), 3.09-2.74 (m, 4H), 2.63 (broad s,1H), 2.21-2.04 (m, 1H), 1.69-1.48 (m, 6H), 1.38-1.24 (m, 9H).

LC/MS (method 7): retention time 2.72 min, 97.6% UV purity (220 nm), m/zmass observed 477.3.

SFC (method 5): retention time 2.1 min, >97% UV purity (220 nm).

Example 8: Preparation of Dodecanoyloxymethyl 1a and 1b

Mixtures of(R)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1-((dodecanoyloxy)methyl)-1,2,2-trimethylpiperazin-1-iumiodide and(S)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1-((dodecanoyloxy)methyl)-1,2,2-trimethylpiperazin-1-iumiodide (1a3; X═I⁻ and 1b3; X═I⁻) and(R)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1-((dodecanoyloxy)methyl)-1,2,2-trimethylpiperazin-1-iumchloride and(S)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1-((dodecanoyloxy)methyl)-1,2,2-trimethylpiperazin-1-iumchloride (1a3; X═Cl⁻ and 1b3; X═Cl⁻) were prepared in a similar manneras 1a1 and 1b1. The synthesis started from4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethylpiperazine(1; 7.00 g) and iodomethyl dodecanoate (3c; 16.8 g) in acetonitrile (49mL) to afford afford ca. 5.5 g crude iodide. This material was purifiedby reverse-phase column chromatography (method 18) followed byion-exchange (method 11) to afford 3.2 g of a mixture of(R)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1-((dodecanoyloxy)methyl)-1,2,2-trimethylpiperazin-1-iumchloride and(S)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1-((dodecanoyloxy)methyl)-1,2,2-trimethylpiperazin-1-iumchloride (1a3; X═Cl⁻ and 1b3; X═Cl⁻).

¹H NMR: 400 MHz Methanol-d₄ 7.45 (s, 1H), 7.31-7.23 (m, 3H), 7.23-7.17(m, 1H), 7.13-7.07 (m, 2H), 6.94 (d, J=8.3 Hz, 1H), 5.52 (broad s, 1H),5.40 (dd, J=3.9, 8.8 Hz, 1H), 4.64-4.55 (m, 1H), 4.47 (broad t, J=7.2Hz, 1H), 3.81-3.64 (m, 1H), 3.56 (broad d, J=14.5 Hz, 1H), 3.11 (d,J=7.5 Hz, 3H), 3.04-2.91 (m, 2H), 2.86-2.75 (m, 2H), 2.57 (dt, J=1.8,7.5 Hz, 2H), 2.19-2.06 (m, 1H), 1.71-1.56 (m, 8H), 1.29 (broad s, 17H),0.93-0.84 (m, 3H).

LC/MS (method 13): retention time 2.66 min, 99.3% UV purity (220 nm),m/z mass observed 567.3.

Example 9: Preparation of Dodecanoyloxymethyl 2a and 2b

Mixtures of(R)-4-((1R,3S)-6-chloro-3-(phenyl-d₅)-2,3-dihydro-1H-inden-1-yl)-1-((dodecanoyloxy)methyl)-2,2-dimethyl-1-(methyl-d₃)piperazin-1-iumiodide and(S)-4-((1R,3S)-6-chloro-3-(phenyl-d₅)-2,3-dihydro-1H-inden-1-yl)-1-((dodecanoyloxy)methyl)-2,2-dimethyl-1-(methyl-d₃)piperazin-1-iumiodide (2a3; X═I⁻ and 2b3; X═I⁻) and(R)-4-((1R,3S)-6-chloro-3-(phenyl-d₅)-2,3-dihydro-1H-inden-1-yl)-1-((dodecanoyloxy)methyl)-2,2-dimethyl-1-(methyl-d₃)piperazin-1-iumchloride and(S)-4-((1R,3S)-6-chloro-3-(phenyl-d₅)-2,3-dihydro-1H-inden-1-yl)-1-((dodecanoyloxy)methyl)-2,2-dimethyl-1-(methyl-d₃)piperazin-1-iumchloride (2a3; X═Cl⁻ and 2b3; X═Cl⁻) were prepared in a similar manneras 1a3 and 1b3. The synthesis started from4-((1R,3S)-6-chloro-3-(phenyl-d₅)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d₃)piperazine(2; 5.60 g) and iodomethyl dodecanoate (3c; 10.5 g) in acetonitrile (39mL) to afford ca. 5 g crude iodide and 3.1 g of a mixture of(R)-4-((1R,3S)-6-chloro-3-(phenyl-d₅)-2,3-dihydro-1H-inden-1-yl)-1-((dodecanoyloxy)methyl)-2,2-dimethyl-1-(methyl-d₃)piperazin-1-iumchloride and(S)-4-((1R,3S)-6-chloro-3-(phenyl-d₅)-2,3-dihydro-1H-inden-1-yl)-1-((dodecanoyloxy)methyl)-2,2-dimethyl-1-(methyl-d₃)piperazin-1-iumchloride (2a3; X═Cl⁻ and 2b3; X═Cl⁻).

¹H NMR: 400 MHz Methanol-d₄ 7.49 (broad s, 1H), 7.27 (d, J=8.3 Hz, 1H),6.94 (d, J=8.3 Hz, 1H), 5.52 (broad s, 1H), 5.46-5.36 (m, 1H), 4.69-4.58(m, 1H), 4.50 (broad t, J=7.5 Hz, 1H), 3.86-3.66 (m, 1H), 3.61 (broad s,1H), 3.16-2.79 (m, 4H), 2.57 (dt, J=1.3, 7.5 Hz, 2H), 2.23-2.07 (m, 1H),1.76-1.51 (m, 8H), 1.47-1.19 (m, 17H), 0.95-0.83 (m, 3H).

LC/MS (method 13): retention time 2.68 min, 98.9% UV purity (220 nm),m/z mass observed 575.4.

Example 10: Preparation of Cyclohexylacetoxymethyl 1a and 1b

Mixtures of(R)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1-((2-cyclohexylacetoxy)methyl)-1,2,2-trimethylpiperazin-1-iumiodide and(S)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1-((2-cyclohexylacetoxy)methyl)-1,2,2-trimethylpiperazin-1-iumiodide (1a4; X═I⁻ and 1b4; X═I⁻) and(R)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1-((2-cyclohexylacetoxy)methyl)-1,2,2-trimethylpiperazin-1-iumchloride and(S)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1-((2-cyclohexylacetoxy)methyl)-1,2,2-trimethylpiperazin-1-iumchloride (1a4; X═Cl⁻ and 1b4; X═Cl⁻) were prepared in a similar manneras 1a1 and 1b1. The synthesis started from4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethylpiperazine(1, 6.00 g) and iodomethyl 2-cyclohexylacetate (3d; 11.9 g) inacetonitrile (42 mL) to afford ca. 8 g crude iodide and 3.2 gHPLC-purified mixture (method 8) of(R)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1-((2-cyclohexylacetoxy)methyl)-1,2,2-trimethylpiperazin-1-iumchloride and(S)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1-((2-cyclohexylacetoxy)methyl)-1,2,2-trimethylpiperazin-1-iumchloride (1a4; X═Cl⁻ and 1b4; X═Cl⁻). This mixture of was separated bychiral SFC (method 9). The two products were purified as before usingmethods 11 and 8 to afford two products:

First eluting isomer: 1.00 g of either(R)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1-((2-cyclohexylacetoxy)methyl)-1,2,2-trimethylpiperazin-1-iumchloride (1a4; X═Cl⁻) or(S)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1-((2-cyclohexylacetoxy)methyl)-1,2,2-trimethylpiperazin-1-iumchloride (1b4; X═Cl⁻).

¹H NMR: 400 MHz Methanol-d₄ 7.57 (broad s, 1H), 7.32-7.26 (m, 3H),7.25-7.19 (m, 1H), 7.15-7.09 (m, 2H), 6.95 (d, J=8.3 Hz, 1H), 5.56(broad s, 1H), 5.45 (d, J=8.8 Hz, 1H), 4.74 (broad s, 1H), 4.57 (broadt, J=7.5 Hz, 1H), 3.84-3.60 (m, 2H), 3.27-2.77 (m, 8H), 2.46 (d, J=7.0Hz, 2H), 2.23 (td, J=7.2, 14.5 Hz, 1H), 1.99-1.47 (m, 12H), 1.39-1.13(m, 3H), 1.12-0.96 (m, 2H)

LC/MS (method 14): retention time 2.85 min, 97.4% UV purity (220 nm),m/z mass observed 509.3.

SFC (method 10): retention time 2.45 min, >99% UV purity (220 nm).

Second eluting isomer: 0.33 g of either(S)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1-((2-cyclohexylacetoxy)methyl)-1,2,2-trimethylpiperazin-1-iumchloride (1b4; X═Cl⁻) or(R)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1-((2-cyclohexylacetoxy)methyl)-1,2,2-trimethylpiperazin-1-iumchloride (1a4; X═Cl⁻).

¹H NMR: 400 MHz Methanol-d₄ 7.51 (s, 1H), 7.33-7.26 (m, 3H), 7.25-7.19(m, 1H), 7.14-7.09 (m, 2H), 6.96 (d, J=8.8 Hz, 1H), 5.56-5.47 (m, 1H),5.46-5.39 (m, 1H), 4.72-4.64 (m, 1H), 4.52 (broad t, J=7.7 Hz, 1H), 3.79(broad s, 1H), 3.62 (broad s, 1H), 3.21-2.77 (m, 8H), 2.46 (d, J=6.8 Hz,2H), 2.26-2.12 (m, 1H), 1.85-1.55 (m, 12H), 1.43-1.16 (m, 3H), 1.12-0.97(m, 2H).

LC/MS (method 15): retention time 3.66 min, 97.7% UV purity (220 nm),m/z mass observed 509.2.

SFC (method 10): retention time 6.41 min, >97% UV purity (220 nm).

Example 11: Preparation of Cyclohexylacetoxymethyl 2a and 2b

Mixture of(R)-4-((1R,3S)-6-chloro-3-(phenyl-d₅)-2,3-dihydro-1H-inden-1-yl)-1-((2-cyclo-hexylacetoxy)methyl)-2,2-dimethyl-1-(methyl-d₃)piperazin-1-iumiodide and(S)-4-((1R,3S)-6-chloro-3-(phenyl-d₅)-2,3-dihydro-1H-inden-1-yl)-1-((2-cyclohexylacetoxy)methyl)-2,2-dimethyl-1-(methyl-d₃)piperazin-1-iumiodide (2a4; X═I⁻ and 2b4; X═I⁻) and(R)-4-((1R,3S)-6-chloro-3-(phenyl-d₅)-2,3-dihydro-1H-inden-1-yl)-1-((2-cyclohexylacetoxy)methyl)-2,2-dimethyl-1-(methyl-d₃)piperazin-1-iumchloride and(S)-4-((1R,3S)-6-chloro-3-(phenyl-d₅)-2,3-dihydro-1H-inden-1-yl)-1-((2-cyclohexylacetoxy)methyl)-2,2-dimethyl-1-(methyl-d₃)piperazin-1-iumchloride (2a4; X═Cl⁻ and 2b4; X═Cl⁻) were prepared in a similar manneras 1a1 and 1b1. The synthesis started from4-((1R,3S)-6-chloro-3-(phenyl-d₅)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d₃)piperazine(2; 6.00 g) and iodomethyl 2-cyclohexylacetate (3d; 11.7 g) inacetonitrile (42 mL) to afford ca. 7.8 g crude iodide and 6 gHPLC-purified (method 8) mixture of(R)-4-((1R,3S)-6-chloro-3-(phenyl-d₅)-2,3-dihydro-1H-inden-1-yl)-1-((2-cyclohexylacetoxy)methyl)-2,2-dimethyl-1-(methyl-d₃)piperazin-1-iumchloride and(S)-4-((1R,3S)-6-chloro-3-(phenyl-d₅)-2,3-dihydro-1H-inden-1-yl)-1-((2-cyclohexylacetoxy)methyl)-2,2-dimethyl-1-(methyl-d₃)piperazin-1-iumchloride (2a4; X═Cl⁻ and 2b4; X═Cl⁻). This mixture was separated bychiral SFC (method 16). The two products were purified as before usingmethods 11 and 8 to afford two products:

First eluting isomer: 1.10 g of either(R)-4-((1R,3S)-6-chloro-3-(phenyl-d₅)-2,3-dihydro-1H-inden-1-yl)-1-((2-cyclohexylacetoxy)methyl)-2,2-dimethyl-1-(methyl-d₃)piperazin-1-iumchloride (2a4; X═Cl⁻) or(S)-4-((1R,3S)-6-chloro-3-(phenyl-d₅)-2,3-dihydro-1H-inden-1-yl)-1-((2-cyclohexylacetoxy)methyl)-2,2-dimethyl-1-(methyl-d₃)piperazin-1-iumchloride (2b4; X═Cl⁻).

¹H NMR: 400 MHz Methanol-d₄ 7.50 (broad s, 1H), 7.30 (broad d, J=8.2 Hz,1H), 6.97 (d, J=8.2 Hz, 1H), 5.54 (broad s, 1H), 5.49-5.41 (m, 1H), 4.66(broad s, 1H), 4.58-4.48 (m, 1H), 3.73 (broad s, 1H), 3.62 (broad s,1H), 3.21-2.74 (m, 5H), 2.47 (d, J=6.8 Hz, 2H), 2.26-2.12 (m, 1H),1.92-1.57 (m, 12H), 1.38-1.17 (m, 3H), 1.14-0.98 (m, 2H).

LC/MS (method 14): retention time 2.68 min, 96.6% UV purity (220 nm),m/z mass observed 517.2.

SFC (method 10): retention time 2.33 min, >97% UV purity (220 nm).

Second eluting isomer: 1.10 g of either(S)-4-((1R,3S)-6-chloro-3-(phenyl-d₅)-2,3-dihydro-1H-inden-1-yl)-1-((2-cyclohexylacetoxy)methyl)-2,2-dimethyl-1-(methyl-d₃)piperazin-1-iumchloride (2b4; X═Cl⁻) or(R)-4-((1R,3S)-6-chloro-3-(phenyl-d₅)-2,3-dihydro-1H-inden-1-yl)-1-((2-cyclohexylacetoxy)methyl)-2,2-dimethyl-1-(methyl-d₃)piperazin-1-iumchloride (2a4; X═Cl⁻).

¹H NMR: 400 MHz Methanol-d₄ 7.48 (broad s, 1H), 7.28 (d, J=8.2 Hz, 1H),6.95 (d, J=8.2 Hz, 1H), 5.49 (broad s, 1H), 5.44-5.38 (m, 1H), 4.64(broad d, J=4.0 Hz, 1H), 4.49 (broad s, 1H), 3.83-3.70 (m, 1H), 3.58(broad d, J=13.2 Hz, 1H), 3.16-2.63 (m, 5H), 2.45 (d, J=6.8 Hz, 2H),2.16 (broad dd, J=6.9, 10.7 Hz, 1H), 1.91-1.51 (m, 12H), 1.43-1.16 (m,3H), 1.13-0.95 (m, 2H).

LC/MS (method 7): retention time 2.99 min, 99.4% UV purity (220 nm), m/zmass observed 517.3.

SFC (method 10): retention time 4.87 min, >97% UV purity (220 nm).

Example 12: Plasma Stability Assay

Frozen human plasma (stored at −80° C.) was thawed in a water bathfollowed by centrifugation at 3200×g for 5 min to remove debris. The pHvalue of the supernatant was then measured and adjusted to 7.4±0.1 byadding 1% phosphoric acid or 1 N sodium hydroxide.

For each test compound, 2 microL of dosing solution (50 microM for testcompounds and 100 microM for positive control; propantheline bromide)were spiked into 98 microL of blank plasma to achieve a finalconcentration of 1 microM test compound and 2 microM positive control.

The test compounds and positive control were incubated in duplicate withhuman plasma (final DMSO concentration <1%) in a water bath at 37° C. atsix different time points (0, 0.5, 1, 2, 4 and 6 hr). At eachcorresponding time point the incubations were terminated by addingappropriate volume of quenching solution to stop the reaction.

Afterwards, the plasma samples were briefly vortexed and subsequentlycentrifuged at 3200×g for 20 min. The supernatant was transferred into a96-well plate and diluted with 200 microL of ultrapure water in theratio of 1:2 prior to LC-MS/MS analysis. The peak area ratios (PAR) ofanalyte/internal standard was used to semi-quantitatively determine theconcentration of test compounds and control compound. The percentage oftest compound remaining at the individual time points relative to the 0minute sample was reported.

In the determination of in vitro elimination constant, ke, of the parentdrug and controls, the analyte/internal standard peak area ratios wereconverted to percentage remaining with the following equation:

${\%\mspace{14mu}{Remaining}} = {\frac{\begin{matrix}{{Peak}\mspace{14mu}{area}\mspace{14mu}{ratio}\mspace{14mu}{of}\mspace{14mu}{analyte}\mspace{14mu}{to}\mspace{14mu}{internal}} \\{{standard}\mspace{14mu}{at}\mspace{14mu}{each}\mspace{14mu}{time}\mspace{14mu}{point}}\end{matrix}}{\begin{matrix}{{Peak}\mspace{14mu}{area}\mspace{14mu}{ratio}\mspace{14mu}{of}\mspace{14mu}{analyte}\mspace{14mu}{to}} \\{{{internal}\mspace{14mu}{standard}\mspace{14mu}{at}\mspace{14mu} t} = 0}\end{matrix}} \times 100\%}$

The percentage formation of metabolite was calculated by theanalyte/internal standard peak area ratios versus TO (absolute) ofmetabolite drug and converted to percentage.

The half-life (T½) of parent drug and control compounds were calculatedfrom a log linear plot of analyte/internal standard peak area ratiosversus time (T½=0.693/ke).

Compounds 1a2, 1b2, 2a2, and 2b2 were incubated in human plasma asdescribed above and half-lives of 0.5-1.5 h were determined with theformation of 15-35% of4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethylpiperazineand4-((1R,3S)-6-chloro-3-(phenyl-d₅)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d₃)piperazine,respectively.

1. A prodrug of4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethylpiperazinein the form of 1a or 1b or4-((1R,3S)-6-chloro-3-(phenyl-d₅)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d₅)piperazinein the form of 2a and 2b

wherein X⁻ is a counter ion selected from the group consisting of halideanion, optionally fluorinated C₁-C₁₀ sulfonate, and optionallyfluorinated linear or branched C₁-C₁₁ carboxylate; and wherein R isselected from the group consisting of linear or branched C₁-C₁₁ alkyland C₃-C₁₀ cycloalkyl; or a pharmaceutically acceptable salt thereof. 2.The prodrug according to claim 1, wherein R is linear or branched C₁-C₁₁alkyl, or a pharmaceutically acceptable salt thereof.
 3. The prodrugaccording to claim 1, wherein R is selected from the group consisting ofmethyl, tertbutyl, n-undecane and cyclohexylmethyl, or apharmaceutically acceptable salt thereof.
 4. The prodrug, or apharmaceutically acceptable salt thereof, according to claim 1, whereinthe pharmaceutically acceptable salt is selected from the groupconsisting of salts formed from hydrochloride acid, hydrobromide acid,phosphoric acid, nitrous acid, sulphuric acid, benzoic acid, citricacid, gluconic acid, lactic acid, maleic acid, succinic acid, tartaricacid, acetic acid, propionic acid, oxalic acid, maleic acid, fumaricacid, glutamic acid, pyroglutamic acid, salicylic acid, saccharin andsulfonic acids.
 5. The prodrug according to claim 1 selected from thegroup consisting of(R)-1-(acetoxymethyl)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethylpiperazin-1-ium,(S)-1-(acetoxymethyl)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1,2,2-trimethylpiperazin-1-ium,(R)-1-(acetoxymethyl)-4-((1R,3S)-6-chloro-3-(phenyl-d₅)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d₃)piperazin-1-ium,(S)-1-(acetoxymethyl)-4-((1R,3S)-6-chloro-3-(phenyl-d₅)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d₃)piperazin-1-ium,(R)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-methyl-1-((pivaloyloxy)methyl)piperazin-1-ium,(S)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-methyl-1-((pivaloyloxy)methyl)piperazin-1-ium,(R)-4-((1R,3S)-6-chloro-3-(phenyl-d₅)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d₃)-1-((pivaloyloxy)methyl)piperazin-1-ium,(S)-4-((1R,3S)-6-chloro-3-(phenyl-d₅)-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1-(methyl-d₃)-1-((pivaloyloxy)methyl)piperazin-1-ium,(R)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1-((dodecanoyloxy)methyl)-1,2,2-trimethylpiperazin-1-ium,(S)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1-((dodecanoyloxy)methyl)Application1,2,2-trimethylpiperazin-1-ium,(R)-4-((1R,3S)-6-chloro-3-(phenyl-d₅)-2,3-dihydro-1H-inden-1-yl)-1-((dodecanoyloxy)methyl)-2,2-dimethyl-1-(methyl-d₃)piperazin-1-ium,(S)-4-((1R,3S)-6-chloro-3-(phenyl-d₅)-2,3-dihydro-1H-inden-1-yl)-1-((dodecanoyloxy)methyl)-2,2-dimethyl-1-(methyl-d₃)piperazin-1-ium,(R)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1-((2-cyclohexylacetoxy)methyl)-1,2,2-trimethylpiperazin-1-ium,(S)-4-((1R,3S)-6-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl)-1-((2-cyclohexylacetoxy)methyl)-1,2,2-trimethylpiperazin-1-ium,(R)-4-((1R,3S)-6-chloro-3-(phenyl-d₅)-2,3-dihydro-1H-inden-1-yl)-1-((2-cyclohexylacetoxy)methyl)-2,2-dimethyl-1-(methyl-d₅)piperazin-1-ium,and(S)-4-((1R,3S)-6-chloro-3-(phenyl-d₅)-2,3-dihydro-1H-inden-1-yl)-1-((2-cyclohexylacetoxy)methyl)-2,2-dimethyl-1-(methyl-d₃)piperazin-1-ium,each of which is combined with a counter ion selected from the groupconsisting of halide anion, optionally fluorinated C₁-C₁₀ sulfonate, andoptionally fluorinated linear or branched C₁-C₁₁ carboxylate; or apharmaceutically acceptable salt thereof.
 6. A pharmaceuticalcomposition comprising any of the prodrugs of claim 1, or apharmaceutically acceptable salt thereof, and one or morepharmaceutically acceptable excipients. 7.-9. (canceled)
 10. A methodfor the treatment of a CNS disease, the method comprising administeringa therapeutically effective amount of a compound according to claim 1 toa patient in need thereof.
 11. The prodrug according to claim 1, whereinR is C₃-C₁₀ cycloalkyl, or a pharmaceutically acceptable salt thereof.12. The prodrug, or a pharmaceutically acceptable salt thereof,according to claim 1, wherein the pharmaceutically acceptable salt isselected from the group consisting of salts formed from methanesulfonicacid, ethanesulfonic acid, toluenesulfonic acid and benzenesulfonicacid.
 13. The prodrug, or a pharmaceutically acceptable salt thereof,according to claim 2, wherein the pharmaceutically acceptable salt isselected from the group consisting of salts formed from hydrochlorideacid, hydrobromide acid, phosphoric acid, nitrous acid, sulphuric acid,benzoic acid, citric acid, gluconic acid, lactic acid, maleic acid,succinic acid, tartaric acid, acetic acid, propionic acid, oxalic acid,maleic acid, fumaric acid, glutamic acid, pyroglutamic acid, salicylicacid, saccharin and sulfonic acids.
 14. The prodrug, or apharmaceutically acceptable salt thereof, according to claim 3, whereinthe pharmaceutically acceptable salt is selected from the groupconsisting of salts formed from hydrochloride acid, hydrobromide acid,phosphoric acid, nitrous acid, sulphuric acid, benzoic acid, citricacid, gluconic acid, lactic acid, maleic acid, succinic acid, tartaricacid, acetic acid, propionic acid, oxalic acid, maleic acid, fumaricacid, glutamic acid, pyroglutamic acid, salicylic acid, saccharin andsulfonic acids.
 15. The prodrug, or a pharmaceutically acceptable saltthereof, according to claim 11, wherein the pharmaceutically acceptablesalt is selected from the group consisting of salts formed fromhydrochloride acid, hydrobromide acid, phosphoric acid, nitrous acid,sulphuric acid, benzoic acid, citric acid, gluconic acid, lactic acid,maleic acid, succinic acid, tartaric acid, acetic acid, propionic acid,oxalic acid, maleic acid, fumaric acid, glutamic acid, pyroglutamicacid, salicylic acid, saccharin and sulfonic acids.
 16. The prodrug, ora pharmaceutically acceptable salt thereof, according to claim 5,wherein the counter ion is selected from the group consisting ofchloride, bromide and iodide.
 17. The prodrug, or a pharmaceuticallyacceptable salt thereof, according to claim 5, wherein the counter ionis selected from the group consisting of mesylate, tosylate,trifluoromethanesulfonate, and nonafluorobutanesulfonate.
 18. Theprodrug, or a pharmaceutically acceptable salt thereof, according toclaim 5, wherein the counter ion is trifluoroacetate.
 19. The prodrug,or a pharmaceutically acceptable salt thereof, according to claim 1,wherein the counter ion is selected from the group consisting ofchloride, bromide, iodide, mesylate, tosylate,trifluoromethanesulfonate, nonafluorobutanesulfonate, andtrifluoroacetate.